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  IN THIS Article
 ::  Material and methods
 ::  Results
 ::  Discussion
 ::  Acknowledgement
 ::  References

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Year : 1980  |  Volume : 26  |  Issue : 2  |  Page : 127-30

Chlorpropamide induced syndrome of inappropriate antidiuretic hormone secretion.







How to cite this article:
Fonseca V A, Deb M M, Gokani S S, Bhandarkar S D. Chlorpropamide induced syndrome of inappropriate antidiuretic hormone secretion. J Postgrad Med 1980;26:127


How to cite this URL:
Fonseca V A, Deb M M, Gokani S S, Bhandarkar S D. Chlorpropamide induced syndrome of inappropriate antidiuretic hormone secretion. J Postgrad Med [serial online] 1980 [cited 2020 Oct 1];26:127. Available from: http://www.jpgmonline.com/text.asp?1980/26/2/127/979



A large number of drugs have been reported to produce the SIADH. There have been several reports of this syndrome complicating therapy of diabetes mellitus with chlorpropamide.[5], [7], [8], [10], [14],[16] The diagnostic criteria of this syndrome are hyponatraemia, continued renal excretion of sodium, absence of dehydration and urine osmolality greater than serum osmolality, in the presence of normal renal and adrenal function.[9]
This study was undertaken to determine the frequency of SIADH in an Indian diabetic population taking chlorpropamide and to determine whether this syndrome contributed in any way to the morbidity of these patients.

  ::   Material and methods Top

One hundred diabetics, well controlled for at least three months on chlorpropamide alone, were selected. Patients taking any other drug were excluded. A careful clinical search was made to exclude C.C.F., hypertension, dehydration and Addison's disease, Patients with abnormal serum creatinine or blood urea nitrogen were excluded.
These 100 patients were questioned about weight gain, drowsiness, headache, anorexia, nausea, vomiting, depression, lethargy, inability to concentrate, confusion and history of coma, symptoms reported to be associated with SIADH.[9]
Serum and urine electrolytes (by flame photometer), serum and urine osmolality (by Fiske Advanced Osmometer), blood urea nitrogen and serum creatinine were estimated in all 100 patients during their out-patient attendance after breakfast.
Twenty-one patients who were willing for further investigations were subjected to a five hour water load test. Each patient was given 20 ml of water per kg. body weight and the urine volume over the next five hours was measured. The creatinine clearance of all these 21 patients was determined and found to be within normal limits.

  ::   Results Top

The symptoms admitted by the patients studied are shown in [Table 1]. In all, 67 patients had one or more of the symptoms enquired about.
No patient had a serum sodium less than 130 mmol/l nor plasma osmolality of less than 280 mosmol/Kg.
[Table 2] shows the details of the 21 patients on whom a water load test was done. Apparently healthy subjects in Bombay excrete 80-120% (Mean 100%, S.D. 10%) of a water load in 5 hours during a standard water load test (Bhandarkar S. D. unpublished results). Sixteen patients showed an abnormality in the excretion of water load (less than 80% excretion) and 13 of them excreted 11-70%. As the table shows, the serum sodium levels and serum osmolality were normal in all patients. The urine sodium varied from 46 mmol/l to 161 mmol/1 and the urine osmolality varied from 174 mosmol,/kg to 854 mosmol/kg.
Thus, although none fulfilled the criteria of SIADH, 16 had abnormal excretion of water load.

  ::   Discussion Top

A drug-induced SIADH secondary to vincristine was first described in 1966 by Fine et al.[6] Hagen and Frawley[8] (1969) were the first to report hyponatraemia following the use of sulphonylurea compounds. Since then, there have been several other reports of this syndrome complicating chlorpropamide therapy in patients with diabetes mellitus.[5], [7], [10], [14], [16] The mechanism of this syndrome is believed to be potentiation of the action of ADH on the renal tubules by an increase in the sensitivity of adenyl cyclase to the hormone.[13]
Hamilton[9] has pointed out that due to the non-specific nature of the symptoms of the syndrome, it may easily be missed. He has stated that the syndrome should be kept in mind when a patient on chlorpropamide complains of drowsiness, headache, anorexia, nausea, vomiting, confusion or lethargy.[9] Sixty seven out of 100 patients questioned admitted one or more of these symptoms. However, none of them fulfilled the criteria for diagnosis of this syndrome as outlined earlier. Thus, it appears that these symptoms are nonspecific.
The frequency of the syndrome as a complication of chlorpropamide therapy is difficult to determine. Weissman et al[16] estimated that approximately 4% of diabetics receiving chlorpropamide may be suffering from the syndrome. Martin and Robinson 12 found that the prevalence of the syndrome was nearly 16%. However, Nisbet[14] believes that it is less common than was originally supposed. Epstein et al[4] claimed that the complication was rare; of 221 patients receiving chlorpropamide, none had a serum sodium below 120 mmol/1 and only two patients has a serum sodium less than 130 mmol/1. By the criteria mentioned earlier, none of the 100 patients investigated by us had the syndrome. The reason for this is not clear. Various theories could be postulated to explain the difference between our findings and those of other authors. One possibility is a genetically determined difference in the sensitivity of the renal tubule to the drug in the Indian population. Another possibility is that our patients may be able to conserve sodium better, as a part of the process of acclimatization to a hot tropical environment. Sodium conservation as a part of acclimatization to a hot environment is well known. [1]. [2], [3], [11] This sodium conservation may be mediated by an increased aldosterone secretion. Increased urinary excretion of aldosterone has been observed in individuals exposed to a hot environment.[1], [15] The observation that 16 out of 21 patients showed an abnormality in the excretion of a water load and that 13 of them excreted less than 70% of a water load is interesting, especially since all these patients had normal serum sodium and osmolality and therefore did not have all the features of the syndrome. This suggests that even while the drug may not cause a full blown picture of the syndrome, it might potentiate the action of ADH on the renal tubule to some extent.

  ::   Acknowledgement Top

We wish to thank the Dean, K. E. M. Hospital and Seth G. S. Medical College, Bombay, for permission to publish this paper.

  ::   References Top

1.Collins, K. J.: Endocrine control of salt and water in hot conditions. Fed. Proc., 22: 716-720, 1963.  Back to cited text no. 1    
2.Desai, N. D., Kulkarni, B. S., Raut, V. S. and Satoskar, R. S.: Total body exchangeable sodium and radio-sodium space in Indians from warm and humid climate. Ind. J. Med. Sci., 21: 300-309, 1967.  Back to cited text no. 2    
3.Dill, D. B.: Salt economy in extreme dry heat. J. Biol. Chem., 100: 755-767, 1933.  Back to cited text no. 3    
4.Epstein, S., Mieghem, W. V . , Simson, E. and Jackson, W. P. U.: Chlorpropamide hyponatraemia. New Engl. J. Med., 286: 785, 1972.  Back to cited text no. 4    
5.Fine, D. and Shedrovilzky, H.: Hyponatraemia due to chlorpropamide; A syndrome resembling inappropriate secretion of anti-diuretic hormone. Ann. Intern. Med., 72: 83-87, 1970.  Back to cited text no. 5    
6.Fine, R. N., Clarke, R. R. and Shore, N. A.: Hyponatraemia and Vincristine therapy. Syndrome possibly resulting from inappropriate anti-diuretic hormone secretion. Amer. J. Dis. Childh., 112: 256-259, 1966.  Back to cited text no. 6    
7.Garcia, M., Miller, 1V1. and Moses, A. M.: Chlorpropamide induced water retention in patients with diabetes mellitus, Ann. Intern. Med., 75: 549-554, 1971.  Back to cited text no. 7    
8.Hagen, G. A. and Frawley, T. F.: Hyponatraemia due to sulphonylurea compounds. J. Lab. Clin. Med., 74: 881, 1969.  Back to cited text no. 8    
9.Hamilton, D. V.: Chlorpropamide-induced inappropriate secretion of antidiuretic hormone. The Practitioner, 220: 469-471, 1978.  Back to cited text no. 9    
10.Hayes, J. S. and Kaye, M.: Inappropriate secretion of anti-diuretic hormone induced by chlorpropamide. Amer. J. Med. Sci., 263: 137-141, 1972.  Back to cited text no. 10    
11.Leithead, C. S.: Water and electrolyte metabolism in the heat. Fed. Proc., 22: 901-908, 1963.  Back to cited text no. 11    
12.Martin, R. J. and Robinson, S. R.: South Med. J., 69: 152'4, 1976. Quoted by Hamilton, D. V.: Chlorpropamide- induced inappropriate secretion of antidiuretic hormone. The Practitioner, 220: 469. 1978.  Back to cited text no. 12    
13.Murase, T. and Yoshida, S.: Mechanism of chlorpropamide action in patients with diabetes insipidus. J. Clin. Endocrinol, and Metab., 36: 174-177, 1973.  Back to cited text no. 13    
14.Nisbet, P.: Chlorpropamide induced hyponatraemia. Brit. Med. J., 1: 904, 1977.  Back to cited text no. 14    
15.Streeten, 13. P., Conn, J. W., Louis, L. H . , Fajans, S. S., Seltzer, H. S . , Johnson, R. D.. Gittler, R. D. and Dube, A. H.: Secondary ildosteronism: Metabolic and adrenocortical responses of normal man to high environmental temperatures. Metabolism, 9: 1071-1092, 1960.  Back to cited text no. 15    
16.Weissman, P. N., Shenkman, L. and Gregerman, R. I.: Chlorpropamide hyponatraemia. New Engl. J. Med., 284: 65-71, 1971.  Back to cited text no. 16    

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Online since 12th February '04
2004 - Journal of Postgraduate Medicine
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